DAGK

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Introduction

Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). As we all know, DG and PA are both very important signal molecules. DG is involved in regulating the activity of a variety of proteins, including chimerins, protein kinase C (PKC), Unc-13, and so on. PA can also activate certain enzymes, including phosphatidylinositol 4-phosphate 5-kinase, and atypical isoforms of PKC. Therefore, DGK is recognized as a key enzyme that regulates and controls various cellular responses by regulating the balance of two lipid messengers. So far, ten subtypes of DGK have been cloned and divided into five groups based on their structural motifs. All DGKs have found two cysteine-rich regions (C1A and C1B domains). These C1 domains of DGKs are homologous to the C1 domains of PKC, which shows DG-dependent protein kinase activity.

All DGKs have a catalytic domain in the C-terminal half of the molecule, the catalytic domains of type II (δ, η, and κ) DGKs are divided into two parts by an insertion. In addition to these domains, different groups also have different structures. Type I DGKs (DGKα, β, and γ) have a recoverin homology (RVH) domain and an EF-hand motif that is considered calcium ion sensors. Type II DGKs (DGKδ, η, and κ) have a pleckstrin homology (PH) domain at the N-terminus and a sterile α motif (SAM) domain at the C-terminus. Type III DGK, DGKϵ, only contains the C1 domain. Type IV DGKs (DGK ζ and ι) have a myristoylated alanine-rich protein kinase C substrate phosphorylation site like region (MARCKS homology domain) between C1 and the catalytic domain and a C-terminal PDZ binding site. V-type DGK, DGKθ, has a domain rich in proline and glycine rich domain and a PH domain that overlaps with the Ras-related domain.

Figure 1. Schematic illustration of DGKs with the phosphorylation sites (Shirai, Y.; Saito, N. 2014)

Each subtype of DGK shows a subtype-specific tissue expression pattern. For example, DGKα is located in oligodendrocytes, and DGKβ, γ, ϵ, ζ, ι, and θ are located in neurons. Among them, DGKβ is expressed in hippocampus, caudate putamen, and cerebral cortex, but not in the cerebellum while DGKγ, θ and ζ are expressed in the cerebellum. DGKδ shows ubiquitous expression. DGKδ plays a key role in insulin resistance in diabetes. DGKs are expressed in large amounts in the brain, but their neuronal function is still unclear for a long time. Due to their enzymatic properties and neuronal functions, DGKs have been widely used in the development of drugs for neuronal diseases.  

Table 1. Characteristics of mammalian DGK subtypes (Shirai, Y.; Saito, N. 2014)

Perspective

DGKs may be involved in spine formation and help improve brain function by controlling membrane lipids and protein-protein interactions, contributing to higher brain functions including memory and emotions.  Studies have found that mTOR and cPKC, which are activated by PA and DG, are involved in the DGKβ-induced neurite induction and branching. On the other hand, there may also be unknown mechanisms such as kinase-independent pathways. For example, recent studies have found that there are kinase-independent pathways in the DGKβ-induced neurite induction and branching.

Due to its important functions, some DGKs can become targets for the treatment of neuronal diseases (including seizure, memory loss, and mood disorders), but there are still no more accurate experiments to verify these drugs for neuronal diseases. More importantly, it is very necessary to find subtype-specific inhibitors and/or activators of each DGK subtype, because DGKs have significant subtype specificity and numerous physiological functions. Recently, Sakane et al. have developed a new high throughput method for screening. DGKs are not only involved in neuronal diseases, but also other diseases including diabetes and cardiovascular diseases, etc. In addition, the relationship between cancer and DGKs has recently been reported. These facts indicate that DGKs can become targets for various diseases, and the research on DGK subtype-specific inhibitors and/or activators will greatly accelerate the development of drugs targeting DGKs for neuronal diseases, diabetes, and cancer.

Figure 2. A schema of functions of DGKs in brain (Shirai, Y.; Saito, N. 2014)